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Frontostriatal circuitry and the tryptophan kynurenine pathway in major psychiatric disorders

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Abstract

Rationale

An imbalance of the tryptophan kynurenine pathway (KP) commonly occurs in psychiatric disorders, though the neurocognitive and network-level effects of this aberration are unclear.

Objectives

In this study, we examined the connection between dysfunction in the frontostriatal brain circuits, imbalances in the tryptophan kynurenine pathway (KP), and neurocognition in major psychiatric disorders.

Methods

Forty first-episode medication-naive patients with schizophrenia (SCZ), fifty patients with bipolar disorder (BD), fifty patients with major depressive disorder (MDD), and forty-two healthy controls underwent resting-state functional magnetic resonance imaging. Plasma levels of KP metabolites were measured, and neurocognitive function was evaluated. Frontostriatal connectivity and KP metabolites were compared between groups while controlling for demographic and clinical characteristics. Canonical correlation analyses were conducted to explore multidimensional relationships between frontostriatal circuits-KP and KP-cognitive features.

Results

Patient groups shared hypoconnectivity between bilateral ventrolateral prefrontal cortex (vlPFC) and left insula, with disorder-specific dysconnectivity in SCZ related to PFC, left dorsal striatum hypoconnectivity. The BD group had higher anthranilic acid and lower xanthurenic acid levels than the other groups. KP metabolites and ratios related to disrupted frontostriatal dysconnectivity in a transdiagnostic manner. The SCZ group and MDD group separately had high-dimensional associations between KP metabolites and cognitive measures.

Conclusions

The findings suggest that KP may influence cognitive performance across psychiatric conditions via frontostriatal dysfunction.

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Data availability

Data will be made available on request.

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Acknowledgements

We warmly thank Professor Nan-kuei Chen (Radiology Medical Research Lab, University of Arizona) for helping with the fMRI preprocessing analysis. We also warmly thank all the participants for their participation in the study.

Funding

This work was supported by the National Natural Science Foundation of China Key Project (81920108018 and 82230046 to TL); the China Brain Project (grant number 2021ZD0200404 to TL); the Key R & D Program of Zhejiang (grant number 2022C03096 to TL); the Project for Hangzhou Medical Disciplines of Excellence & Key Project for Hangzhou Medical Disciplines; the Science & Technology Development Project of Hangzhou (202004A11 to TL, A20210013 to SGL); the Medical Science & Technology Plan Projects of Zhejiang Province (2022KY990 to SGL); and the Leading Healthcare Talents of Zhejiang Province; the Monique H. Bourgeois Chair in Developmental Disorders and Graham Boeckh Foundation (Douglas Research Centre, McGill University) (to LP). LP acknowledges salary award from the Fonds de recherche du Quebec-Sante ́ (FRQS).

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Author notes

  1. Sugai Liang and Liansheng Zhao contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, Affiliated Mental Health Centre & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310013, Zhejiang, China

    Sugai Liang, Wanjun Guo, Yan Xu, Xiaojing Li, Wei Deng & Tao Li

  2. Mental Health Centre & Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Liansheng Zhao, Peiyan Ni, Qiang Wang, Jia Cai & Shiwan Tao

  3. Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, H4H1R3, Canada

    Lena Palaniyappan

  4. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, N6A5K8, Canada

    Lena Palaniyappan

  5. Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Zhejiang, 310000, Hangzhou, China

    Tao Li

  6. NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Zhejiang, 310063, Hangzhou, China

    Tao Li

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  1. Sugai Liang
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  2. Liansheng Zhao
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  11. Lena Palaniyappan
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  12. Tao Li
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Correspondence to Lena Palaniyappan or Tao Li.

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LP reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; and investigator-initiated educational grants from Janssen Canada, Sunovion, and Otsuka Canada outside the submitted work. All other authors report no relevant conflicts.

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Liang, S., Zhao, L., Ni, P. et al. Frontostriatal circuitry and the tryptophan kynurenine pathway in major psychiatric disorders. Psychopharmacology 241, 97–107 (2024). https://doi.org/10.1007/s00213-023-06466-9

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